Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the regulation of the activity of amino acid transport system L in the JAR human placental choriocarcinoma cell line by agents which are known to modulate the activities of three different classes of protein kinases, A-kinase, C-kinase and CaM-kinase. The system L activity was measured by determining the uptake of leucine in these cells, grown as confluent monolayers. Leucine uptake in these cells was predominantly Na(+)-independent, was stimulated by lowering the extracellular pH and was inhibited by hydrophobic neutral amino acids. These characteristics demonstrate that uptake of leucine in this cell line occurs primarily via system L. Treatment of the cells with cholera toxin and forskolin, agents which are known to elevate intracellular cAMP levels, did not have any effect on the activity of system L. 4 beta-Phorbol 12-myristate 13-acetate, an activator of C-kinase, but not the inactive analogue 4 alpha-phorbol 12,13-didecanoate, caused a significant stimulation of system L. The involvement of C-kinase in the phorbol ester-induced stimulation was supported by the finding that staurosporine, an inhibitor of C-kinase, effectively blocked the stimulation. Calmodulin antagonists, calmidazolium, W-7 and CGS 9343 B stimulated system L activity markedly. The potency of these antagonists was in the following order: calmidazolium greater than CGS 9343 B greater than W-7. This stimulatory effect was specific for system L because systems A and ASC were not stimulated by these agents. The stimulation caused by these agents was primarily due to an increase in the maximal velocity, the apparent Km of the system being only minimally affected. It is concluded that the activity of amino acid transport system L in the JAR human placental choriocarcinoma cell line is stimulated by C-kinase, inhibited by CaM-kinase and unaffected by A-kinase.
...
PMID:Modulation of the activity of amino acid transport system L by phorbol esters and calmodulin antagonists in a human placental choriocarcinoma cell line. 132 10

The effects of phosphorylation of ribosomal protein S6 by two different protein kinases, the cAMP-dependent protein kinase and the mitogen-stimulated S6 kinase, or translation of globin mRNA in a reconstituted system and on binding of globin mRNA to 40 S ribosomal subunits were examined. The cAMP-dependent protein kinase incorporated 1.5 mol of phosphate/mol of 40 S ribosomal subunits. Phosphorylation of S6 by the cAMP-dependent protein kinase had no effect on binding of 3' terminus-labeled globin mRNA to 40 S ribosomal subunits. [3H]Leucine incorporation with 40 S ribosomal subunits phosphorylated by the cAMP-dependent protein kinase was identical to that observed with nonphosphorylated 40 S ribosomal subunits, although on occasion, a slight inhibition (less than 10%) was observed; there was no effect on the rate of synthesis of either the alpha or beta chains of globin. Phosphorylation with the mitogen-stimulated S6 kinase (2.5 mol/mol) did not alter binding of globin mRNA to 40 S ribosomal subunits; however, translation of globin mRNA in the reconstituted protein-synthesizing system was stimulated up to 4-fold over that observed with nonphosphorylated subunits. Synthesis of both the alpha and beta chains of globin was enhanced by phosphorylation as shown by electrophoretic analysis. Since the sites phosphorylated by the mitogen-stimulated S6 kinase are identical to those observed in vivo in response to insulin and growth-promoting compounds, the data support the hypothesis that enhanced synthesis of specific proteins may be due to phosphorylation of S6 and that differential phosphorylation of S6 can alter translation of natural mRNA.
...
PMID:Phosphorylation of ribosomal protein S6 by cAMP-dependent protein kinase and mitogen-stimulated S6 kinase differentially alters translation of globin mRNA. 381 53

Plasmodium species possess developmentally regulated ribosomal RNA (rRNA) genes. This report describes the expression and gene structure of the largest subunit of P. falciparum RNA polymerase I (RNAPI), which is responsible for the synthesis of rRNA. The RNAPI largest subunit gene was present as a single copy gene on chromosome 9. Three exons encode the 2910-amino acid RNAPI polypeptide (340 140 Da). A comparison of Plasmodium, Trypanosoma, and Saccharomyces cerevisiae nuclear RNAP largest subunits identified conserved amino acid positions and class-specific amino acid positions. Novel amino acid insertions were found between RNAPI conserved regions A and B (region A'), D and DE1 (region D'), DE2 and E (region DE2'), and F and G (region F'). Leucine zipper domains were found within regions D', DE2, and DE2'. A novel serine-rich repeat domain, a domain with homology to the C-terminal domain of eukaryotic upstream binding factor (UBF), and 4 highly conserved casein kinase II (CKII) Ser/Thr phosphorylation motifs were found within a 127-amino acid sub-region of enlarged region F'. The novel RNAPI serine-rich repeat contained a conserved motif, Ser-X3-Ser, which was also identified in the serine-rich repeat domains of the P. falciparum RNAPII and RNAPIII largest subunits, as well as within a highly homologous serine-rich repeat from trophozoite antigen R45. The results of this molecular analysis indicate that phosphorylation and dephosphorylation mechanisms regulate the activity of P. falciparum RNAPI.
...
PMID:Molecular characterization of the largest subunit of Plasmodium falciparum RNA polymerase I. 825 31

Leucine-rich nuclear export signals (NESs) are recognized by the NES receptor exportin 1 and are central to the export of multiple shuttling proteins and RNAs. The export of messenger RNA in vertebrates was, however, thought to occur by a different pathway, because inhibition by injection of a synthetic Rev NES conjugate could not be demonstrated. Here we find that peptide conjugates composed of the NES of either protein kinase A inhibitor protein (PKI) or the HIV-1 Rev protein, when coupled to human serum albumin, are potent inhibitors of mRNA and small nuclear RNA export. These results provide direct evidence that mRNA export in vertebrates depends on interactions between an NES and its cognate NES receptors. PKI NES conjugates are significantly more efficient at inhibiting RNA export than are REV NES conjugates, indicating that different NESs may have different abilities to promote protein and RNA export. Surprisingly, an expected control conjugate containing the mutant Rev NES sequence M10 strongly inhibited the export of intronless dihydrofolate reductase mRNA. Nuclear injection of NES peptide conjugates led to mislocalization to the nucleus of 10-20% of the cytoplasmic Ran GTPase-binding protein (RanBP1) indicating that RanBP1 shuttles between the nucleus and the cytoplasm via an NES pathway. These results demonstrate that in vertebrates the export of mRNA, like that of small nuclear RNA, 5S rRNA, and transport factors such as RanBP1, employs NES-mediated molecular machinery.
...
PMID:Inhibition of mRNA export in vertebrate cells by nuclear export signal conjugates. 940 23

Mixed lineage kinase-3 (MLK-3) is a mitogen-activated kinase kinase kinase that mediates stress-activating protein kinase (SAPK)/c-Jun NH2-terminal kinase activation. MLK-3 and other MLK family kinases are characterized by the presence of multiple protein-protein interaction domains including a tandem leucine/isoleucine zipper (LZs) motif. Leucine zippers are known to mediate protein dimerization raising the possibility that the tandem leucine/isoleucine zippers may function as a dimerization motif of MLK-3. Using both co-immunoprecipitation and nonreducing SDS-polyacrylamide gel electrophoresis, we demonstrated that MLK-3 forms disulfide bridged homo-dimers and that the LZs motif is sufficient for MLK-3 homodimerization. We next asked whether MLK-3 utilizes a dimerization-based activation mechanism analogous to that of receptor tyrosine kinases. We found that dimerization via the LZs motif is a prerequisite for MLK-3 autophosphorylation. We then demonstrated that co-expression of Cdc42 lead to a substantial increase in MLK-3 dimerization, indicating that binding by this GTPase may induce MLK-3 dimerization. Moreover, the LZs minus form of MLK-3 failed to activate the downstream target SAPK, and expression of a MLK-3 LZs polypeptide was found to block SAPK activation by wild type MLK-3. Taken together, these findings indicate that dimerization plays a pivotal role in MLK-3 activation.
...
PMID:Dimerization via tandem leucine zippers is essential for the activation of the mitogen-activated protein kinase kinase kinase, MLK-3. 982 70

Regulation of translation of mRNAs coding for specific proteins plays an important role in controlling cell growth, differentiation, and transformation. Two proteins have been implicated in the regulation of specific mRNA translation: eukaryotic initiation factor eIF4E and ribosomal protein S6. Increased phosphorylation of eIF4E as well as its overexpression are associated with stimulation of translation of mRNAs with highly structured 5'-untranslated regions. Similarly, phosphorylation of S6 results in preferential translation of mRNAs containing an oligopyrimidine tract at the 5'-end of the message. In the present study, leucine stimulated phosphorylation of the eIF4E-binding protein, 4E-BP1, in L6 myoblasts, resulting in dissociation of eIF4E from the inactive eIF4E.4E-BP1 complex. The increased availability of eIF4E was associated with a 1.6-fold elevation in ornithine decarboxylase relative to global protein synthesis. Leucine also stimulated phosphorylation of the ribosomal protein S6 kinase, p70(S6k), resulting in increased phosphorylation of S6. Hyperphosphorylation of S6 was associated with a 4-fold increase in synthesis of elongation factor eEF1A. Rapamycin, an inhibitor of the protein kinase mTOR, prevented all of the leucine-induced effects. Thus, leucine acting through an mTOR-dependent pathway stimulates the translation of specific mRNAs both by increasing the availability of eIF4E and by stimulating phosphorylation of S6.
...
PMID:Leucine regulates translation of specific mRNAs in L6 myoblasts through mTOR-mediated changes in availability of eIF4E and phosphorylation of ribosomal protein S6. 1020 76

Amino acid availability is known to regulate diverse cell processes including the activation of p70 S6 kinase, initiation factors involved in mRNA translation, gene expression and cellular amino acid uptake. Essential amino acids, in particular the branched-chain amino acids (e.g. leucine), have been shown to be the dominant players in mediating these effects, although the precise nature by which they regulate these processes remain poorly understood. In this study we have investigated the mechanisms involved in the leucine-induced modulation of p70 S6 kinase and addressed whether this kinase participates in the up-regulation of the System A amino acid transporter in L6 muscle cells. Incubation of muscle cells that had been amino acid-deprived for 1 h with L-leucine (2 mM) led to a rapid (>2-fold) activation of p70 S6 kinase, which was suppressed by both wortmannin and rapamycin. Consistent with this finding, addition of leucine caused a rapid ( approximately 5-fold) but transient stimulation of phosphatidylinositol 3-kinase (PI3K). PI3K activation was inhibited by wortmannin and was not dependent upon insulin receptor substrate-1 activation. Unlike stimulation by insulin, activation of neither protein kinase B nor p42/p44 mitogen-activated protein kinase accompanied the leucine-induced stimulation of PI3K. However, the leucine-induced activation of PI3K and p70 S6 kinase did result in the concomitant inactivation of glycogen synthase kinase-3 (GSK-3). Leucine enhanced System A transport by approximately 50%. We have shown previously that this stimulation is protein-synthesis-dependent and in the current study we show that it was blocked by both wortmannin and rapamycin. Our findings indicate that PI3K and the mammalian target of rapamycin are components of a nutrient signalling pathway that regulates the activation of p70 S6 kinase and induction of System A in L6 cells. The activation of this pathway by leucine is also responsible for the inactivation of GSK-3, and this is likely to have important regulatory implications for translation initiation.
...
PMID:L-leucine availability regulates phosphatidylinositol 3-kinase, p70 S6 kinase and glycogen synthase kinase-3 activity in L6 muscle cells: evidence for the involvement of the mammalian target of rapamycin (mTOR) pathway in the L-leucine-induced up-regulation of system A amino acid transport. 1094 49

The objectives of the present study were twofold: 1) to determine whether leucine is unique among the branched-chain amino acids (BCAA) in its ability to stimulate protein synthesis in skeletal muscle of food-deprived rats; and 2) to investigate whether changes in muscle protein synthesis after leucine administration involve a signaling pathway that includes the protein kinase mammalian target of rapamycin (mTOR). In the first set of experiments, food-deprived (18 h) male rats (200 g) were orally administered saline or 270 mg valine, isoleucine or leucine. In the second set of experiments, food-deprived rats were injected intravenously with rapamycin (0.75 mg/kg), a specific inhibitor of mTOR, before leucine administration. Only leucine stimulated protein synthesis in skeletal muscle above saline-treated controls (P: < 0.05). Furthermore, leucine was most effective among the BCAA at enhancing phosphorylation of eukaryotic initiation factor (eIF), 4E binding protein 1 (4E-BP1) and the 70-kDa ribosomal protein S6 kinase (S6K1). Leucine-dependent hyperphosphorylation of 4E-BP1 increased the availability of eIF4E to form the active eIF4G.eIF4E complex. To a lesser extent, isoleucine also enhanced phosphorylation of 4E-BP1 and S6K1. Rapamycin inhibited protein synthesis in both leucine-treated and food-deprived rats. Additionally, rapamycin prevented the stimulatory effects of leucine on eIF4E availability for binding eIF4G and inhibited leucine-dependent phosphorylation of S6K1. The data demonstrate that leucine is unique among the BCAA in its ability to stimulate protein synthesis in muscle of food-deprived rats. We show for the first time that leucine-dependent stimulation of translation initiation in vivo occurs via a rapamycin-sensitive pathway.
...
PMID:Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway. 1101 66

Control of protein synthesis by amino acid availability is an active and centrally important area of research that has produced several recent advances in our understanding of how these substrates serve not only as precursors but also as signaling molecules. One particularly noteworthy advance is the identification of the unique specificity of leucine in signaling to stimulate protein synthesis in skeletal muscle. Leucine mediated signaling results in a stimulation of initiation of mRNA translation and involves increases in the phosphorylation status of the translational repression 4E-BP1 and the ribosomal protein S6 kinase S6K1. It requires sustained activation of the mammalian target of rapamycin protein kinase. Leucine, however, also signals to stimulate protein synthesis in skeletal muscle by a mammalian target of rapamycin protein kinase independent (i.e. rapamycin insensitive) pathway, suggesting that the amino acid may signal through multiple pathways. Furthermore, leucine signaling in skeletal muscle differs from that in liver, suggesting that various responses may be tissue specific. Finally, there continues to be active research on the beneficial effects of glutamine as a unique supplement in catabolic circumstances. In this case, however, the signaling properties and mechanism of action of glutamine remain as an unsolved mystery.
...
PMID:Control of protein synthesis by amino acid availability. 1179 Sep 48

Upstream stimulating factors, USF-1 and -2, are members of the evolutionary conserved basic-Helix-Loop-Helix-Leucine Zipper transcription factor family. The ubiquitously expressed USF-1 and -2 proteins of respectively 43 kDa and 44 kDa interact with high affinity to cognate E-box regulatory elements (CANNTG) which are particularly represented over the genome. The USF transcription factors are key regulatory elements of the transcriptional machinery mediating recruitment of chromatin remodelling enzymes, interacting with co-activators and members of the pre-initiation complex (PIC). Furthermore, transcriptionnal activity and DNA-binding of the USF proteins can be modulated by multiple ways including phosphorylation by distinct kinases (p38, protein kinase A and C, cdk1 and PI3Kinase), homo or heterodimerization formation and DNA modification of the E-box binding motif (methylation, SNP). Taken together, these parameters render very complex the understanding of the USF-dependent gene expression regulation. USF transcription factors have thus been involved as key regulators of a wide number of gene regulation network including stress and immune response, cell cycle and proliferation. This review will thus focus on general aspect of the USF transcription factors and their implications in some regulatory networks.
...
PMID:[USF as a key regulatory element of gene expression]. 1638 22


1 2 3 4 5 Next >>

---